Device And Method To Slow Or Stop The Heart Temporarily

ABSTRACT

Implantable cardiac drug delivery systems. The systems are installed endocardially into a chamber in the heart, and are variously capable of delivering anti-arrhythmia agents into the heart wall, and into the epicardial space outside the heart, and into other chambers in the heart through the septa of the heart.

This application is a continuation of U.S. application Ser. No.09/969,712, filed Oct. 2, 2001, which is a continuation of U.S.application Ser. No. 09/257,887, filed Feb. 25, 1999, which is now U.S.Pat. No. 6,296,630, which is a continuation-in-part of U.S. applicationSer. No. 09/057,060 filed Apr. 8, 1998.

FIELD OF THE INVENTION

The inventions described below relate to the field of cardiovascularsurgery, including systems and methods for temporarily introducing aconduction block between the atria and ventricles in a mammalian heartfor the purpose of fine control over cardiac contraction. This wouldallow surgeons to temporarily stop the heart, and/or alter the heartrate to reduce the motion associated with cardiac contraction. Thisprovides substantial advantage to delicate surgical techniques that areperformed on the heart.

BACKGROUND OF THE INVENTION

Atrial fibrillation is a form of heart disease that afflicts millions ofpeople. It is a condition in which the normal contraction of the heartis interrupted, primarily by abnormal and uncontrolled action of theatria of the heart. The heart has four chambers: the right atrium, rightventricle, the left ventricle, and the left atrium. The right atriumpumps de-oxygenated blood from the vena cava to the right ventricle,which pumps the blood to the lungs, necessary for return flow ofde-oxygenated blood from the body. The right atrium contracts to squeezeblood into the right ventricle, and expands to suck blood from the venacava. The contractions normally occur in a controlled sequence with thecontractions of the other chambers of the heart. When the right atriumfails to contract, contracts out of sequence, or contractsineffectively, blood flow within the heart is disrupted. The disruptionof the normal rhythm of contraction is referred to as an arrhythmia. Thearrhythmia known as atrial fibrillation can cause weakness due toreduced ventricular filling and reduced cardiac output, stroke due toclot formation in a poorly contracting atria (which may lead to braindamage and death), and even other life threatening ventriculararrhythmias.

Atrial defibrillator is a therapy being developed for atrialfibrillation. Atrial defibrillators are typically implantable electricaltherapy devices which deliver defibrillating energy to the atrium toterminate arrhythmias. They sense the electrical activity of the atriumand deliver an electrical shock to the atrium when the electricalactivity indicates that the atrium is in fibrillation. Electricaldefibrillation has two major problems: the therapy causes substantialpain and has the potential to initiate a life threatening ventriculararrhythmia. The pain associated with the electrical shock is severe andunacceptable for many patients. Unlike electrical ventriculardefibrillators where the patient loses consciousness prior to receivingtherapy, the patient who suffers an atrial arrhythmia is conscious andalert when the device delivers electrical therapy.

The potential exists for inappropriate induction of ventricularfibrillation by the shock intended to defibrillate the atrium. Theinduction of ventricular fibrillation has great potential to result indeath in just a few minutes if no intervening therapy is provided.Careful algorithms to deliver shocks to the periods in the ventricularcontraction cycle when the heart is not susceptible to shock inducedventricular fibrillation have been developed to reduce the potential ofthis risk. If the problem of patient pain can be overcome, atrialdefibrillators could be used in a large portion of the patientpopulation that suffer from atrial fibrillation.

Pharmacological Atrial Defibrillators

For some time, doctors have treated atrial fibrillation with drugsinjected intravenously or administered orally. Recent literaturedescribes the potential for the delivery of drugs to the heart on demandto terminate arrhythmias. The concept has been suggested for use in theatrium to treat atrial fibrillation. Arzbaecher, Pharmacologic AtrialDefibrillator and Method, U.S. Pat. No. 5,527,344 (Jun. 18, 1996)describes a pharmacological atrial defibrillator and method forautomatically delivering a defibrillating drug into the bloodstream of apatient upon detection of atrial arrhythmias in order to terminate theatrial arrhythmias. Arzbaecher teaches that unspecified defibrillatingdrugs should be injected into the bloodstream with a large initial dosefollowed by delivery of a continuous smaller dose (this is the“two-compartment pharmacokinetic model” discussed in the Arzbaecherpatent). By delivering agents to a blood vessel and maintaining atherapeutic level of drugs in the blood stream, Arzbaecher requiressystemic effects to be achieved in order to terminate atrialarrhythmias. In other words, if drugs injected according to Arzbaecherare to have any effective concentrations within the heart, a largeamount must be injected in the blood stream to ensure that an adequatedose will be delivered to the affected area of the heart. While thedrugs are in the blood stream, they are available throughout the body tocause side effects on all other organs.

There are several disadvantages to the transient introduction ofsystemic drug levels by an implantable device. Systemic effectsresulting from such delivery may result in detrimental effects toventricular cardiac conduction. These detrimental effects could be lifethreatening. The large amount of drugs required for systemic delivery oftherapeutic doses demands a larger, less comfortable device than smallerdosages would allow. The large quantity of drug in the implantablereservoir of such a system is potentially more dangerous if it developsa leak or is ruptured. Such a large single dosage will require areservoir that requires frequent follow ups for refilling post therapyby a clinician. Lastly, the large quantities of drug required to obtaintherapeutic levels in the entire body may cost substantially more thanthat required to treat a specific site within the heart. The systemdescribed by Arzbaecher has one primary advantage over electrical atrialdefibrillation: the delivery of therapy to terminate an arrhythmia doesnot cause patient pain, and some recent abstracts have appeared in theliterature which suggest that this technique is viable. See Arzbaecher,et al., Development Of An Automatic Implanted Drug Infusion System ForThe Management Of Cardiac Arrhythmias, 76 IEEE Proc. 1204 (1991); Bloem,et al., Use Of Microprocessor Based Pacemaker To Control An ImplantableDrug Delivery System, Computers in Cardiology 1 (1993); Bloem, et al.,Microprocessor Based Automatic Drug Infusion System For Treatment OfParoxysmal Atrial Fibrillation, 26S J. Electrocardiogr. 60 (1993); andWood, et al., Feedback control of antiarrhythmic agents, in MolecularInterventions and Local Drug Delivery, (WB Saunders 1995).

Drug delivery directly into the heart has been proposed for otherconditions. In my own prior patent, Altman, Implantable Device for theEffective Elimination of Cardiac Arrythmogenic Sites, U.S. Pat. No.5,551,427 (Sep. 3, 1996) I describe an implantable substrate for localdrug delivery at a depth within the heart. The patent shows animplantable helically coiled injection needle which can be screwed intothe heart wall in the ventricles and connected to an implanted drugreservoir outside the heart. This system allows injection of drugsdirectly into the wall of the heart by merely the injection of drugsthrough the skin into the reservoir. The patent also shows a helicalcoil coated with a coating which releases drug into the myocardium. Thisdrug delivery may be performed by a number of techniques, among theminfusion through a fluid pathway, and delivery from controlled releasematrices at a depth within the heart. Co-pending application Ser. No.08/881,685 by Altman and Altman, describes some additional techniquesfor delivering local pharmacological agents to the heart.

Other implanted drug delivery systems have been proposed. Levy, Systemfor Controlled Release of Antiarrhythmic Agents, U.S. Pat. No. 5,387,419(Feb. 7, 1995), describes the placement of controlled release matriceson the surface of the epicardium (on the outside of the heart) fordelivery of antiarrhythmic agents, but all dosage forms described arefor steady state drug delivery and do not address the advantages oftransient drug delivery from an implantable epicardial structure. Inaddition, the device described by Levy does not address the criticalissue of surgical access to the epicardial surface.

Controlled release matrices are drug polymer composites in which apharmacological agent is dispersed throughout a pharmacologically inertpolymer substrate. Sustained drug release takes place via particledissolution and slowed diffusion through the pores of the base polymer.Prior work has shown that antiarrhythmic therapy administered byepicardial application of controlled release polymer matrices iseffective in treating and preventing ventricular arrhythmias in canineventricular tachycardia model systems [Siden, et al., EpicardialControlled Release Verapimil Prevents Ventricular Tachycardia EpisodesInduced by Acute Ischemia in a Canine Model, 19 J. CardiovascularPharmacology 798 (1992).] This work shows the viability of controlledrelease therapy delivered locally for the treatment of arrhythmias. Thiswork is identical to that described by Levy above in that drug deliverystructures are placed on the outside surface of the heart during openheart surgery. No delivery at a depth within the heart is described,there is no discussion of how one would implant the structurenon-invasively, and there is no discussion of how one would deliverdrugs upon demand to the heart.

Cardiac Pacing

In the past, devices implanted into the heart have been treated withanti-inflammatory drugs to limit the inflammation of the heart caused bythe wound incurred while implanting the device itself. For example,pacing leads have incorporated steroid drug delivery to limit tissueresponse to the implanted lead, and to maintain the viability of thecells in the region immediately surrounding the implanted device.Berthelson, Medical Electrical Lead Employing Improved PenetratingElectrode, U.S. Pat. No. 5,002,067 (Mar. 26, 1991) describes a helicalfixation device for a cardiac pacing lead with a groove to provide apath to introduce anti-inflammatory drug to a depth within the tissue.The groove does not provide a patent fluid pathway to a depth within theheart, no tube end to end is described, and the device is designed forpacing the heart. No descriptions of using antiarrhythmic agents orother approaches are described.

Moaddeb, Myocardial Steroid Releasing Lead, U.S. Pat. No. 5,324,325(Jan. 24, 1994) describes a myocardial steroid releasing lead whose tipof the rigid helix has an axial bore which is filled with a therapeuticmedication such as a steroid or steroid based drug. There is no fluidpathway from the proximal end of the catheter, the drug deliverystructure is limited in its size, the device is designed for cardiacpacing. Moaddeb describes a reservoir that is small in that it fillsonly the core region of the distal portion of a helix historicallyformed of 0.010 inch diameter to 0.012″ diameter wire.

Vachon, Implantable Stimulation Lead Having an Advanceable TherapeuticDrug Delivery System, U.S. Pat. No. 5,447,533 (Sep. 5, 1995) and U.S.Pat. No. 5,531,780 (Jul. 2, 1996) describe pacing leads having a styletintroduced anti-inflammatory drug delivery dart and needle which isadvanceable from the distal tip of the electrode. No end to end tube isprovided, and no means for transient delivery of agents in animplantable setting is provided.

Cardiac Ablation

The infusion of different fluids to a depth within the myocardium hasbeen described in the patent literature as being useful for ablation.Lesh, Cardiac imaging and ablation catheter, U.S. Pat. No. 5,385,148(Jan. 31, 1995) describes a cardiac imaging and ablation catheter inwhich a helical needle may be used to deliver fluid ablative agents,such as ethanol, at a depth within the tissue to achieve ablation. Leshproposes permanently killing the tissue with a one time application ofethanol such that the heart is permanently damaged, not controlled. Inone embodiment he does describe the potential of temporarily deadeningthe tissue with either lidocaine or iced saline solution, but this ismerely in preparation of killing the tissue. The entire patent hereteaches away from implantable materials and applications as thefundamental device use is for acute ablation procedures. No means fortransient delivery of agents in an implantable setting is provided.

Mulier, Method and Apparatus for Ablation, U.S. Pat. No. 5,405,376 (Apr.11, 1995), Method and Apparatus for R-F Ablation, U.S. Pat. No.5,431,649 (Jul. 11, 1995); and Method for R-F Ablation, U.S. Pat. No.5,609,151 (Mar. 11, 1997) each describe a hollow helical delivery needleto infuse the heart tissue with a conductive fluid prior to ablation tocontrol the lesion size produced. In addition delivery of an agent toaffect cardiac conduction to evaluate an ablation site, and delivery ofRF energy to the helical needle are disclosed. In all embodiments thedevice is described as an acute use ablation catheter using differenttechniques. No means for transient delivery of agents in an implantablesetting is provided.

Cardiovascular Restenosis

Igo, Apparatus And Method For Transpericardial Delivery Of Fluid, U.S.Pat. No. 5,634,895 (Jun. 3, 1997) shows a technique for delivering drugslocally to different regions of the surface of the heart and within thepericardial sac via a subxiphoid surgical route, for treating vascularthrombosis and restenosis. The subxiphoid surgical route requires openchest surgery, and penetration of the pericardial sac. Such invasiveprocedures can be complicated by pericarditis and pericardial tamponade.No techniques for less invasive delivery of bioactive agents to thesurface of the heart or into the pericardial space are described. Nosystems for transient delivery, or transient delivery upon demand aredescribed. No techniques for delivering antiarrhythmic agents orterminating atrial arrhythmias are addressed.

Antiarrhythmic Drugs

There are a number of viable pharmacologic therapies that are alsoavailable. Drugs that predominantly affect slow pathway conductioninclude digitalis, calcium channel blockers, and beta blockers. Drugsthat predominantly prolong refractoriness, or time before a heart cellcan be activated, produce conduction block in either the fast pathway orin accessory AV connections including the class IA antiarrhythmic agents(quinidine, procainimide, and disopyrimide) or class IC drugs (flecamideand propafenone). The class III antiarrhythmic agents (sotolol oramiodarone) prolong refractoriness and delay or block conduction overfast or slow pathways as well as in accessory AV connections. Temporaryblockade of slow pathway conduction usually can be achieved byintravenous administration of adenosine or verapamil. [Scheinman,Supraventricular Tachycardia: Drug Therapy Versus Catheter Ablation, 17Clinical Cardiology II-11 (1994)]. Other agents such as encamide,diltiazem, and nickel chloride are also available.

Drugs currently used for antiarrhythmia control can actually killpeople. The Cardiac Arrhythmia Suppression Trial showed that specificagents delivered systemically resulted in substantially higher mortalityrates than those individuals receiving no drugs at all. [The CardiacArrhythmia Suppression Trial (CAST) Investigators, The effect ofencamide and flecamide on mortality in a randomized trial of arrhythmiasuppression after myocardial infarction, 321 N. Engl. J. Med. 406(1989). Echt, et al., Mortality and morbidity in patients receivingencamide, flecamide, or placebo—the Cardiac Arrhythmia SuppressionTrial, 324 N. Engl. J. Med. 781 (1991).] This is likely due to theproblematic pro-arrhythmia effects of systemic drug delivery.Minimization of dose by local transient drug delivery has potential toeliminate the side effects of these antiarrhythmic agents. There is aneed to improve pharmacological therapy for the treatment of arrhythmiasby providing for local delivery of these and other agents to regionswithin the heart tissue.

There are embodiments of this invention which incorporate noninvasivesurgical techniques for delivering drugs to the pericardial space andovercoming the difficulties of the invasive sub-xiphoid proceduredescribed by Igo. In order to develop these techniques it is importantto touch on the prior art regarding pericardial access and delivery.

Pericardial Access and Delivery

There are a number of approaches for placing devices epicardially.Crosby, Apparatus for cardiac surgery and treatment of cardiovasculardisease, U.S. Pat. No. 4,181,123 (Jan. 1, 1980) and Method And ApparatusFor Permanent Epicardial Pacing Or Drainage Of Pericardial Fluid AndPericardial Biopsy, U.S. Pat. No. 4,319,562 (Mar. 16, 1982) and Chin, etal., Method And Apparatus For Providing Intrapericardial Access AndInserting Intrapericardial Electrodes, U.S. Pat. No. 5,033,477 (Jul. 23,1991) to disclose methods for placing electrodes in contact with theheart muscles from within the pericardial space without the need for athoracotomy. Access to the pericardial space is gained via a sub xiphoidapproach. This involves penetrating the chest wall below the xiphoidprocess.

The sub xiphoid route has several disadvantages. First, because thepericardial sac which surrounds the heart is a tight fitting fibrousmembrane, the pericardial space is so small that it is difficult topenetrate the sac without also puncturing, and thereby damaging theheart itself. Second, accessing the heart via a subxiphoid route entailsa high risk of infection. These are likely to account for the failure ofthese methods to be adopted in common clinical practice.

Several patents, including Elliott, et al., Method For TransvenousImplantation Of Objects Into The Pericardial Space Of Patients, U.S.Pat. No. 4,884,567 (Dec. 5, 1989) and Elliott, Defibrillator System WithCardiac Leads And Method For Transvenous Implantation, U.S. Pat. No.4,946,457 (Aug. 7, 1990) and Cohen, et al., Travenously PlacedDefibrillation Leads, U.S. Pat. No. 4,998,975 (Mar. 12, 1991) haveproposed methods for transvenous implantation of electrodes into thepericardial space. A catheter is introduced through a vein to the rightatrium where the lateral wall is penetrated in order to introduceelectrodes into the pericardial space. A major problem encountered bythese methods is how to penetrate the lateral atrial wall withoutpuncturing the tight fitting pericardium.

The methods of these patents attempt to solve this problem throughseveral elaborate schemes. One scheme involves using complex cathetersto attach to the lateral wall and to pull it back away from thepericardium prior to penetrating the atrial wall in order to avoidpuncturing the pericardium. Another approach involves injecting a fluidinto the pericardial space to distend the pericardium away from thelateral atrial wall prior to penetrating the wall.

Cohen, Method and System for Implanting Self Anchoring EpicardialDefibrillation Electrodes, U.S. Pat. No. 4,991,578 (Feb. 12, 1991)discloses a method for implanting epicardial defibrillation electrodesinto the pericardial space via the subxiphoid route. As discussed above,it is difficult to penetrate the pericardial sac via the sub xiphoidroute without also puncturing and thereby damaging the heart itself.Like the method discussed directly above, the '578 patent disclosesinjecting a fluid into the pericardial space or attaching and pulling ona catheter to distend the pericardial sac away from the heart.

Cohen, Transvenously Placed Defibrillation Leads Via An Inferior VenaCava Access Site And Method Of Use, U.S. Pat. No. 4,991,603 (Feb. 12,1991) discloses a method for implanting defibrillation electrodes incontact with epicardial or pericardial tissue from an inferior vena cavaaccess site. A hole is made in the inferior vena cava and a catheter istransvenously inserted into the inferior vena cava and out through ahole into the chest cavity adjacent to the heart. The catheter thenpierces the pericardial sac to access the pericardial space. The risk ofdamaging the heart muscle remains high with this method.

The pericardial sac has been used for containment of pharmacologicalagents for a number of years in experimental settings, but delivery hasrequired open chest surgery to access the pericardial space. Ellinwood,Apparatus And Method For Implanted Self-Powered Medication Dispensing,U.S. Pat. No. 4,003,379 (Jan. 18, 1977) and Ellinwood, Self-PoweredImplanted Programmable Medication System And Method, U.S. Pat. No.4,146,029 (Mar. 27, 1979) disclose an implantable medication dispensingapparatus which is adapted to dispense drugs to the pericardial sac overa long period of time, for example to prevent arrhythmias. The Ellinwoodpatents do not teach a method for routing drugs to the pericardial sac.Epicardial delivery of pharmacological agents to the heart is similar tothat described in Igo, Apparatus And Method For TranspericardialDelivery Of Fluid, U.S. Pat. No. 5,634,895 (Jun. 3, 1997) whichdescribes a balloon catheter for sub xiphoid access. Levy, System forcontrolled release of antiarrhythmic agents, U.S. Pat. No. 5,387,419(Feb. 7, 1995) describes implantable control release matrices. Verrier,Method For Transvenously Accessing The Pericardial Space Via The RightAuricle For Medical Procedures, U.S. Pat. No. 5,269,326 (Dec. 14, 1993)describes a technique for accessing the pericardium through the rightatrial appendage and describes the possibility of infusing thepericardium with antiarrhythmic agents.

No systems or techniques for local drug delivery to the epicardialsurface of the heart upon demand have been described. In addition, nomeans of creating a viable atriotomy closure after transatrialimplantation of devices has been described. Further, no means has beenprovided for hybrid local drug delivery therapies involving electricaltherapy and ablative therapy for the treatment of arrhythmias.

Cardiac Bypass

There are two general types of cardiac bypass graft procedures: stoppedheart procedures and beating heart procedures. Traditional bypass andits minimally invasive counterpart developed by Heartport, Inc. inRedwood City, Calif., USA involve stopping the heart with a cardioplegiasolution and performing circulatory support by cardiopulmonary bypass.Although excellent success has been achieved with conventional cardiacbypass grafting employing cardiopulmonary bypass for circulatorysupport, the major causes of mortality and morbidity are due to the useof cardiopulmonary bypass as well as manipulation of the aorta by eithercross clamping or placement of proximal grafts that lead toatherosclerotic cerebral emboli. Cardiopulmonary bypass introduces wellknown adverse effects such as hemodilution, stroke, renal insufficiency,coagulopathic bleeding and incitement of the systemic inflammatoryresponse. [M. J. Mack, International Journal of Cardiology, 62 Suppl. 1,1997, S73-S79.] In addition, cardiopulmonary bypass has the disadvantagein that it accounts for a substantial portion of the expensiveprocedural cost. The technology of cardiopulmonary bypass is describedin recent patents devising new methods for managing cardioplegic fluidssuch as U.S. Pat. Nos. 5,423,769; 5,423,749; 5,609,571; 5,643,191;5,702,358; 5,540,841.

Beating heart cardiac bypass surgery, such as the “MIDCAB” proceduredeveloped by CardioThoracic Systems, Portola Valley, Calif. eliminatescardiopulmonary bypass and its inherent disadvantages, but it has itsown complications. Beating heart surgery requires the surgeon to performdelicate techniques on a heart that is beating and full of blood, makingthe procedure much less precise and controllable. Some of thesedifficulties have led to reservations on the part of some physiciansregarding both the “midcab” approach as well as the “port access”approaches for minimally invasive cardiac surgery. [Lawrence I. Bonchekand Daniel J. Ullyot: Minimally Invasive Coronary Bypass A DissentingOpinion, Circulation, 1998; 98: 495-497.] Advantages of beating heartsurgery has led some to attempt the development of complicated surgicalcompensation techniques to eliminate the perception of heart motion forthe surgeon and improve the precision of the procedure. Others havedeveloped methods of physically stabilizing the heart with eitherdevices such as the Medtronic Octopus or less expensive devices formedin the operating suite using wet cotton tape [Vincenzo Lucchetti andGianni D. Angeini: An Inexpensive Method of Heart Stabilization DuringCoronary Artery Operations without Cardiopulmonary Bypass, Ann. Thorac.Surg. 1998; 65:1477-8.]. Altman, in pending U.S. application Ser. No.09/057,060 has described an approach between stopped heart cardiacsurgery and beating heart cardiac surgery, which will be developedfurther here.

SUMMARY OF THE INVENTION

Several inventions described below permit local transient therapy forarrhythmias. Drugs or other anti-arrhythmia agents may be delivered intoone or more regions of the atrial or ventricular wall to controlarrhythmia of the atrium or ventricle with devices implanted into thechest, including a drug delivery catheter with a tip for implantationinto the heart wall and a drug reservoir implanted in the chest. Thedevices can deliver drugs into the wall of the heart, into the leftatrium through a catheter which is implanted in the right atrium, andinto the left ventricle which is implanted in the right ventricle. Thedevices may be combined with other therapies such as implantabledefibrillators and cardiac pacemakers. The devices may also be used totransiently created a long linear lesion within the atrium or used toaugment the effects of a region of permanent ablation transiently.Different embodiments of the systems described may be used together.

The devices and techniques used for local transient therapy may also beto stop the heart for extended periods, temporarily and intermittentlyproviding the physical stability of the heart required for bypasssurgery. This approach falls between stopped heart cardiac surgery andbeating heart cardiac surgery. With acute use catheter systems the heartmay be temporarily stopped or markedly slowed. Such induced bradycardiawould provide a quiescent heart for very short periods so that delicatesurgical procedures may be performed. Procedures as common and asimportant as suturing and performing distal anastamosis during bypasssurgery are examples of techniques that would be improved by suchslowing of the heart. By providing a system to slow or stop conductionwithin the heart, a systemic dosage to eliminate or reduce ventricularautomaticity, and a temporary pacing wire, the surgeon will be able toslow or stop the heart to improve the control and precision of thesurgical techniques performed. In the preferred embodiment conduction isstopped or slowed between the atria and the ventricles, but it could bealtered at other locations such as the sino-atrial node.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is an overview of an implantable cardiac drug delivery system.

FIGS. 1 a through 1 d are detail views of the system of FIG. 1.

FIGS. 1Ea through 1F illustrate a new use of the system of FIG. 1.

FIG. 2 a is an overview of an implantable epicardial drug deliverysystem.

FIGS. 2 b through 2 d are detail views of the system of FIG. 2 a.

FIGS. 2 e through 2 i illustrate catheters for transatrial access to theepicardial space.

FIG. 2J illustrates a helical catheter for transatrial access to theepicardial space.

FIG. 2K illustrates an epicardial patch drug delivery system deployedfrom inside the right atrium.

FIGS. 2L through 2O illustrate deployable epicardial patch drug deliverysystems.

FIGS. 2P through 2Qb are detail views of the system of FIG. 2 k.

FIG. 2R illustrates an epicardial patch drug delivery system deployedfrom inside the right atrium.

FIG. 2S is a detail view of the system of FIG. 2R.

FIG. 3A is a view of an endocardial catheter installed in the rightventricle for trans-septal injection of drugs into the left ventricle.

FIG. 3B illustrates the expected concentration of drugs in the heartwhen delivered according to the method illustrated in FIG. 3A.

FIG. 3C is a view of an endocardial catheter installed in the rightatrium for trans-atrial septum injection of drugs into the left atrium.

FIG. 4 illustrates a method of creating long region of block in theright atrium with a catheter.

FIGS. 4A and 4B show details of the catheter of FIG. 4.

FIG. 5 illustrates the system of filling a drug reservoir to be usedwith the various catheters.

FIGS. 6A and 6B illustrate transient drug delivery catheters incombination with implantable defibrillators.

FIGS. 7A and 7B illustrate methods of transiently delivering drugs inconjunction with creating long linear lesions in the right atrium usingan implanted drug delivery catheter.

FIG. 8 is a simplified overall view of the system with endovascularinfusion catheter and endovascular pacing wires connected to thepatient's heart;

FIG. 9A shows a timing diagram of the pacing and infusion systemsshowing a first embodiment of the operation of the system;

FIG. 9B shows a timing diagram of the pacing and infusion systemsshowing a second embodiment of the operation of the system;

FIG. 10 is a simplified overall view of the system with epicardialinfusion catheter and epicardial pacing wires connected to the patientsheart; and

FIG. 11 shows a partially cross sectional view of an epicardialpenetrating fluid delivery system.

DESCRIPTION OF INVENTION

The description of this invention will be broken down into three partswhich inter-relate to one another: (I) the method and devices for localdelivery to the heart, (II) the methods and devices for transientdelivery of agents to the local drug delivery systems described, andlastly (III) hybrid therapies of such delivery systems and transientdelivery techniques combined with other therapies.

Part I: Method and Devices for Local Delivery to the Heart

Delivery from a Penetrating Structure

One embodiment for extremely local delivery of agents to the myocardiuminvolves a penetrating structure that has a fluid pathway to a depthwithin the myocardium for local infusion of pharmacological agents ondemand. Such implantable infusion devices are described in Altman, U.S.Pat. No. 5,551,427 as well as in a pending patent application U.S.patent application Ser. No. 08/881,685 filed by Altman and Altman. Bothof these should be incorporated here by reference.

For example, a single point source of pharmacological agents deliveredto a depth within the atrial tissue will enable a region of atrium to bepharmacologically modified while the systemic doses are extremely small.This will act as a region of slowed conduction on which the wave frontsassociated with atrial fibrillation will be terminated. Unlike thetransient effects of a paced site, a site infused with drug will haveslowed conduction for a substantial period of time. The longer the drugis infused to the site, the larger the region of inactive atrium willbe. Very small doses can be delivered to specific regions of tissue toterminate arrhythmias. Systemic effects will be minimized. The quantityof agents will be minimized, as will reservoir size and number ofphysician follow-ups.

FIG. 1 shows a detailed drawing of a technique described substantiallyin Altman, U.S. Pat. No. 5,551,427, as well as in a pending patentapplication U.S. patent application Ser. No. 08/881,685 filed by Altmanand Altman. Shown here is a subcutaneously implanted fluid pump 1 havinga plurality of silicone septii 2 and 3 on its upward facing surface tofacilitate the filling of drug reservoirs within pump 1. Also shown onthe surface of pump 1 is a pressure switch 4 which enables the patientto mechanically turn on the pumping mechanism when judged appropriate.Pump 1 is connected to catheter 5 which travels transvenously by way ofthe subclavian vein (not shown) through the superior vena cava 7 andinto the right atrium 6 which is shown in a cut away view. Theseimplantation techniques are well known to those familiar with theplacement of implantable cardiac leads. The penetrating drug deliverystructure, shown here as helix 15 on the end of catheter 5 is in fluidconnection with pump 1 such that drugs can be delivered directly to adepth within the atrial wall tissue. The region within the atrium ofimplantation specified may vary from patient to patient based on thecharacteristics of the atrial arrhythmia being treated. Here it is shownplaced in the intra atrial septum which has been described as importantfor the termination of atrial fibrillation.

FIG. 1A shows the distal end of catheter 5 shown in FIG. 1. Catheterbody 5 may enclose helical wire or cabled wire conductors for monitoringthe electrical activity of the heart or delivering pacing energy whichis coupled to hollow fixation structure 15 which delivers drugs to adepth within the heart tissue 10. The progression of the drug transport20 from the site of the drug delivery helix 15 can be monitored duringimplantation in a number of ways. Either pacing thresholds can bemeasured which will be higher and correlate to a larger infused volume,or endocardial electrophysiology mapping can be performed if desired.

Another means for evaluating and confirming device placement positioninvolves delivering contrast such as Renographin™ from the proximal endof the catheter such that it is released at the distal end near wherethe penetrating structure is placed within the heart wall performing aventricologram or an atriogram. Such contrast delivery may occur from aguide catheter, from a separate dedicated lumen within the catheter drugdelivery system (not shown), or from a separate adjacent cathetersystem. Further, the drug delivery lumen may be flushed with contrast toconfirm that the device is in its appropriate location, designated bythe appearance of contrast stain under fluoroscopy.

An enlarged view of this drug delivery lead is shown in FIG. 1B. Here,hollow fixation structure 15 is shown to have a number of apertures 25along its length, and be connected on its proximal end to both a tube 35for drug delivery and a helical coil 40 for the measurement ofelectrical signals from the heart and the delivery of pacing energy.Structure 30 is made of an electrically conductive material andstabilizes the hollow drug delivery structure and allow for itsconnection to the conductive coil 40.

FIG. 1C shows another embodiment very similar to FIG. 1A except here,the penetrating structure 45 is composed of two elements. In theexpanded view shown in FIG. 1D the two elements are a fixation helix 50and a centrally located needle 55 which is porous over some region. Itshould be clear that it would be very easy to design needle 55 so thatit is not centrally located. This hollow needle 55 is connected to thetube 35, and is also connected electrically to the coil 40 and the helix50. It would be straightforward to make the needle or the helix the solepenetrating conductive element connected to the coil 40.

FIG. 1Ea and FIG. 1Eb show another embodiment in partial cross sectionthat is similar to FIG. 1A. Here, a stylet wire 1 is inserted into coil40 and is used for steering the catheter structure to a particularlocation as well as for deploying penetrating helix 15 for infusingtherapeutic fluid agents. Adjacent to coil 40 is a drug delivery tube 2which wraps helically around coil 40 and is advanced in a region 7 overthe hollow tube or needle 8 which allows for fluid agents to bedelivered either to a depth within the tissue, or through the tissue.Stylet 1 is able to transmit torque to distally located structure 11 byhaving the stylet's distal cross section have one axis longer than theother, such as an oval or rectangle and by having structure 11 be shapedsimilarly such that stylet 1 fits within distal structure 11. Heredistal structure 11 is shown to be press fit onto the outside of coil 40and to the inside of fixation helix 15 shown here to have a hollow crosssection 9. Other means of joining these structures such as crimping,swaging, welding, brazing, and bonding are also possible. Further, thedistal structure 11 may have different cross sectional shapes along itslength to provide for attachment, torque transmission, and electricalcontinuity to fixation structure 15. Upon transmission of torque todistal structure 11, the helix 15 advances through structure 12 and outthe distal end of the catheter to engage the tissue (not shown). Thehelical wrapping of drug delivery tube 2 distends as shown by thedifference in FIGS. 1Ea and 1Eb such that the fluid connections to thepenetrating structure and the proximal connections (not shown) are notstressed. A distensible fluid pathway such as that shown could belocated at different regions along the catheter body, and not just atthe distal end as shown here. By placing it at the distal end, abi-lumen tubing could be used along the length of the catheter until theregion where the distensible drug delivery tubing is located, and anappropriate transition (not shown) to a single lumen tubing such as isshown could be implemented.

FIG. 1F shows a view similar to that shown in 1C, except now the drug isdelivered adjacent to a blood vessel 60 such that the drug can percolateacross the vessel wall and enter into the blood pool that feeds thislocal tissue 10. For example, in the treatment of supraventriculararrhythmias, a catheter placed in the right atrium may be implanted inthe free heart wall such that its drug delivery structure may deliver tovessels such as the right coronary artery (RCA), the sinus node branchof the RCA, the conus branch of the RCA, the atrioventricular nodebranch of the RCA, and the posterior descending interventricular branchof the RCA. The flow from the catheter forces retrograde flow up regionsof the capillaries up the arterioles and into the larger coronaryartery. The drugs delivered in the coronary artery are then distributedto portion of the myocardium that is supplied by the coronary artery.

Delivery from an Epicardial Structure

FIG. 2A shows an intact heart 65 with ventricles 66, and right atria 71and left atria 72. Two epicardial drug delivery patches 70 and 75 coverthe right atria 71 and left atria 72, respectively. These patches areshown to be connected to separate but identical thin drug deliverycatheters 80 a and 80 b which connect the drug delivery patch structureto the implantable pump 76 which is located subcutaneously in thepectoral region. Drug delivery patches are placed over the atria 71 and72 to minimize the drug delivery to the ventricles and to maximize thedelivery to the atria, although it is clear that the opposite scenariois also possible. Drug delivery catheters 80 a and 80 b contain a fluidpathway from drug delivery patches 70 and 75 for the infusion of agentsupon demand. Catheters 80 a and 80 b may also contain electricalconductors which connect to the drug delivery patches to either performelectrical measurements on the activation of the heart, stimulate theheart, or facilitate delivery from the drug delivery structure byopening some electromechanical valve in the distal region.

FIG. 2B shows a side view of these same patch drug delivery systems inwhich tube 80 allows the flow of fluid agents to the thin space 95 whichserves as a plenum, communicating with a fluid resistant mesh 85. Thefluid resistant mesh 85 serves as a diffusing medium which allows thesmall volume of drug in space 95 to be uniformly distributed over thesurface area of the patch as it is delivered. In this way, a largesurface of the heart is treated simultaneously. Mesh 85 could also be arate limiting membrane. The rate limiting membrane could be made ofePTFE with small pores such that the drug distributes more readily overthe surface of the rate limiting barrier inside the drug delivery patchthan it does through the rate limiting barrier. This will prevent all ofthe fluidic agent from being delivered at the point where it enters thelarge surface of delivery patch. Such rate limiting membranes andmaterials are well known in the field of transdermal drug deliverysystems, but have not been used in cardiac drug delivery systems.Alternatively, the barrier could be a thin hydrogel or other materialthrough which the delivery would be required to diffuse more slowly.There is a rim 90 around the drug delivery surface defined by mesh 85such that the patch may be sewn onto the surface of the heart, or to theinside of the pericardial sac such that the drug delivery surface is incontact within the epicardium.

FIG. 2C shows yet another embodiment of this patch drug delivery systemapproach which includes an electrically conductive surface. Hereelectrically conductive Titanium or Platinum mesh 100 is in contact withthe heart such that electrical signals on the surface of the heart orelectrical energy can be delivered to the heart. The mesh is installedon the patch over the rate limiting membrane 85 (not shown). Catheterbody 110 includes both a fluid pathway for drug delivery and theelectrical conductor which connects to mesh 100. Rim 90 is provided tosuture the patch to either the epicardium or the inside of thepericardial sac.

FIG. 2D is a sectional view of the patch drug delivery electrode shownin FIG. 2C that shows electrically conductive mesh 100 is connected atcrimp 115 to conductor cable 120. In addition, fluid agents may traveldown tube 125 within catheter body 110 to drug space 95 for uniformdistribution through mesh 85.

Although shown as one large electrode used for delivering uniform energyto a large surface of tissue, many smaller electrodes could beincorporated in such a design for more precise local measurements of theheart's electrical activity, and local energy delivery. Suchmulti-electrode systems for epicardial placement have been described inthe fields of electrical defibrillation and multi-site pacing.

The patch structures shown in FIGS. 2A, 2B, 2C, and 2D can be placed bymany of the techniques described in the prior art. Many of the lessinvasive surgical techniques for heart access are viable such as the subxiphoid approach. The patches may be delivered endovascularly through atransvenous approach in which the patches are delivered to thepericardial space in a collapsed form and deployed to their larger finalform once within the pericardial space. The specific descriptions oftransvenous access to the pericardial space here shall focus on asolution left incompletely solved in Verrier, Method for TransvenouslyAccessing the Pericardial Space via the Right Auricle For MedicalProcedures, U.S. Pat. No. 5,269,326 (Dec. 14, 1993). The scope of thisinvention is not meant to be limited by this specificity, as alltechniques referenced for transvenous access to the pericardium may beused. Although many techniques have been described in the prior art forcrossing the atria or the vena cava to access the pericardial space,none of them solves the problem of the trans-atrial placement of animplantable device with subsequent wound closure. More importantly, noneof the devices provide a means for delivering antiarrhythmic agents tothe pericardial space and the surface of the heart transiently when anarrhythmic event is present.

The patches shown placed over the atria in FIG. 2 a are placed with arelatively noninvasive trans-thoracic procedure in which a smallincision is made between the ribs and the pericardium cut and enteredwith laparoscopic and microsurgical tools. The patches are placed intheir appropriate places using the techniques similar to the placementof epicardial defibrillation patch leads, and the rim 90 (more clearlyillustrated in FIGS. 2B and 2C) is sutured to hold it in place, such asto either the visceral or parietal pericardium. The pericardial space isthen closed, and the proximal catheters 80 a and 80 b are tunneledthrough the fascia to the region where the drug delivery pump is to beplaced, typically in the subcutaneous region over the pectoral muscle.The catheters 80 are connected to the pump, and then the pump is placedwithin the subcutaneous pocket and the wounds are closed. Subsequent toplacement, the pump reservoir can be refilled by transcutaneousinjection into silicone septum 77.

Installation of local atrial drug delivery systems can be accomplishedwithout open chest surgery, and only requires an atriotomy in the rightatrial appendage. FIG. 2E shows a simple cylindrical transvenouscatheter body 230 penetrating a region of atrial myocardium 200 from theendocardial side 199 to the pericardial side 201 of the myocardium.Flanges 205 and 210 are mechanically attached to catheter body 230 andshown placed on either side of the penetrated atrial wall 200. Flanges205 and 210 are connected to one another and the interspersed atrialtissue 200 by a ring of small staples, two of which are shown as 215 aand 215 b. The flange structures provide reinforcement to the thinatrial tissue to provide stability for the closing staples. Catheter 230has a distal end 220 which lies in the pericardial space and allows forinfusion of the pericardium with pharmacological agents through lumenports 225.

FIG. 2F shows an isometric view of the same catheter system shown inFIG. 2E without the presence of atrial tissue. Clearly the larger crosssectional area of the flaps 205 and 210 for securing the catheter to theatrial wall tissue make it desirable to have these structurescollapsible. Although two such flaps 205 and 210 are shown in thisfigure, it is clear that one or even no flaps may be used in differentembodiments.

FIG. 2G shows such a system with a non deployed collapsed single flap230. Flaps could be made out of materials such as expandedpolytetrafluoroethylene (ePTFE), silicone, Dacron, and combinations ofthese materials possible through lamination, calendering, and othertechniques. In this figure the flap 230 is intended to be made out ofePTFE and be molded in its center to the catheter body at its leadingedge 236. The flap 230 is pulled back and folded along fold lines 232 toits non deployed collapsed position.

Delivery of the catheter system shown in FIG. 2G can be performed with avariety of endoscopic techniques. One approach uses a monorail tip lumenon the distal end 220 of the in-dwelling catheter, such that the entiredelivery catheter can be passed over a smaller guide wire type structurethat has been used to penetrate the right atrial wall. In thisembodiment, the catheter is implanted with a short stylet which does notprotrude from the end of the catheter until the region where penetrationof the atrium is desired. A sharp and short penetrating region of thestylet is then advanced from the distal end of the catheter structure,the catheter advanced through the atrial wall, and the distallyprotruding stylet removed. Here, the deployment of the flaps isperformed by catching trailing edge 234 lip on the atrial myocardium.The catheter is inserted down through the atrial wall into thepericardial space such that the entire flap 230 advances into thepericardial space. Upon pulling back on the catheter the flap deploys inthe pericardial space. Alternatively, the orientation of the flap isreversed such that the advancement of a leading edge lip causes thecatheter flap 230 to deploy in the atrial endocardial space. One flapwith each orientation facilitates the location of a flap on either sideof the atrial myocardium. Radio opaque bands located on the catheterbody at different locations also help with visualization underfluoroscopy.

A second approach for delivery of such a drug delivery catheter systemcould be accomplished with a larger peel away catheter. The largecatheter is advanced to the region for crossing the atrial wall, and asecond centrally located catheter with a sharpened tip is used topenetrate and cross the atrial wall. After the large peel away catheterhas been advanced across the atrial wall, the centrally located catheterwith a sharpened tip is removed, and the drug delivery catheter isadvanced to the pericardial space. Here, the presence of the larger peelaway catheter can be used to control the deployment of the flaps on thecatheter body. In a similar technique to that described above, the flapscould be deployed by pulling the proximally located flap lip 232 againstthe opening of the peel away catheter for deployment. Flaps on bothsides of the atrial wall are deployed in an identical fashion, and thepresence of radio opaque markers would add greatly to the positioningtechniques.

FIG. 2H shows a similar catheter system to that shown in FIG. 2G, exceptthere are two deployable catheter flaps 235 and 240, both with trailingedge lips 245 and 250. In another embodiment, flap 240 would have atrailing edge lip 250 as shown, and flap 235 has a leading edge lip.Further, the proximal flap 235 may be designed to slide on the catheter230 to facilitate the stapling process. The larger peel away guidecatheter could be useful for positioning deployed flaps for subsequentsurgical stapling.

FIG. 2I shows a cross section of a stapler catheter 260 advanced aroundthe transatrial catheter 230 such that the stapler comes into contactwith an endocardial flap 205 and advances it against the atrial wall200. Such staplers would simultaneously provide a number of staples orsutures around the periphery of the catheter structure such that itrepairs the atriotomy. Staples can then be delivered around theperiphery of catheter body 230 to provide fixation of catheter 230 and aviable repair of the penetrated atrial wall 200. In addition, contactsensors 270, 275, 280 and 285 could be used to know that the catheter isin contact with at least the endocardial flap 205 and that flap 205 isfully deployed. By having a ring of conductive material shown in sectionas contact points 275 and 285 in the outside of flap 205, the staplercould monitor electrical continuity between two or morecircumferentially placed electrodes 270 and 280. Continuity would implythat the flaps are deployed and that the staples may be effectivelydelivered.

FIG. 2J shows another embodiment of the transatrial pericardialplacement of a catheter for both delivery of drugs and electricalstimulation of the myocardium. Here catheter 288 enters the right atrium305 via the superior vena cava 290 and exits the right atrium 305 viathe right atrial appendage. External catheter flap 295 is shown withstaples 300 securing the catheter and effecting the repair of thepenetrated atrium. Cylindrical catheter 288 is advanced such that aseries of electrodes can surround the heart along the catheters helicalpath. This view reveals a large number of electrodes 385, 370, 355, 320,330, and 335 placed around the heart. In addition, drug delivery ports380, 310, 315, 360, 325, and 350 are shown such that they also surroundthe heart. There are many different therapies that can be achieved withsuch a system. This example is meant to be instructive rather thanspecific. For electrical stimulation, a number of electrodes could beused with an endocardial return electrode for multi-site pacing, atrialdefibrillation, and ventricular defibrillation. The different electrodescould also be used for sensing activity in different regions of theheart and combined with diagnostic algorithms in implantable electricaldevices (not shown). Such multielectrode catheters have an extensivehistory in the field of cardiac electrophysiology. The multiple drugdelivery ports could be connected to different lumens within thecatheter body 288, or could all be connected to a common lumen.

FIG. 2K shows another embodiment of the transatrial pericardialplacement of a device for both delivery of drugs and electricalstimulation of the myocardium. Here, a deployable patch system is shownplaced over the ventricles. Here, larger surface area electrodes 415 and420 are shown within a large drug delivery patch. As before, thecatheter 401 enters the heart from the superior vena cava 402 andpenetrates the right atrium 305. The proximal end of the catheter 401 isconnected to a subcutaneously placed implantable pump and electricalstimulation device 403. Device 403 is shown with two silicone septii 404and 405, used for filling the internal reservoir with pharmacologicalagents.

FIG. 2L shows one embodiment of this deployable patch structure in crosssection where it is partially deployed. Arms 470 and 460 are wrappedaround catheter body 450 and over one another such that they generateshadow area coverage shown in FIG. 2M when deployed. Deploying such astructure is readily done with simple mechanical techniques.

For example, FIGS. 2N and 2O show a stylet mechanism for deploying thepatch shown in FIGS. 2K, 2L and 2M. Here, a simple thin wire mechanismwith five hinge joints 480, 490, 500, 510, and 520 is advanced down thelumen of the patch structure to deploy the patch. FIG. 2O shows howconcerted movement of stylet arms 525, 585, and 575 will result in theexpansion of a planar wire structure within the deployable epicardialpatch forcing it to expand. Other simple mechanisms and manipulationsdescribed in the art may also be used.

As another example, FIGS. 2P, 2Qa, and 2Qb show a rolled epicardialpatch structure for distributed drug delivery to the epicardial surface.In FIG. 2P, the rolled patch structure 600 is attached to a catheter 610that allows for the transport of drugs, and potentially the presence ofelectrical conductors (not shown) to connect to the rolled patch 600.The patch is advanced through the opening in the atrium by a coveringtubular structure 620 from which it is advanced and deployed. Thistubular delivery catheter is essentially the same as the peel awaycatheter system which has already been described. FIG. 2Qa shows adeployed patch 600 connected to catheter body 610 which is shown here toonly have a lumen for drug delivery 615. It is clear to those familiarwith the art that electrical conductors could be present as well. Patch600 is shown to consist of a number of channels 640 connected by one ormore transverse channels 650. Although many geometries are viable forthe transverse channel, the angled pitch of the transverse channel willresult in a shape that may more readily be rolled to a uniform diameterfor delivery. Drug would pass down lumen 615 of body 610 and intochannels 640 and 650 to be spread uniformly within the patch structurebefore being dispensed to the heart surface. FIG. 2Qb shows the samepatch structure in cross section with channels 640, body 610, andmolding 630. Here, a rate controlling barrier 660, such as could beformed from a microporous filter, membrane, mesh, or other structurewill allow drug molecules within the transport fluid to migrate to thesurface of the heart tissue. However, the resistance of the ratecontrolling surface 660 is greater than that through the channels 640,and the drug will be delivered relatively uniformly to the surface ofthe tissue to be treated.

FIG. 2R shows two similar patches 670 and 680 over the left and rightatria 690 and 700. Here, these dual patches come from a singletransatrial catheter body 710. This single lead body facilitates theclosure and repair of the right atrial appendage or other penetratedtissue after device implantation. Here also, the implantable pump system681 is shown implanted on the patient's right side. For crossing theatrium, different surgeons may prefer either a right or left accessroute. This will determine in which side of the body the device isimplanted.

FIG. 2S shows one potential delivery means in which the fork 720 takesplace prior to the junction of the lead body 710 and the proximal patch670. Proximal patch 670 is wrapped around distal catheter body 730 whichis connected to distal patch 680.

Delivery Through a Septum of the Heart

Another embodiment for local cardiovascular drug delivery, which hasparticular potential for the transient termination of arrhythmias isshown in FIG. 3A. Here, a catheter system similar to that shown in FIG.1A without the pores 20 along the length of hollow fixation structure15, is implanted such that drug can be directly infused into the leftside of the heart from a device which dwells in the right side of theheart.

FIG. 3A shows a drug delivered through the ventricular septum. Catheter145 is implanted in the right ventricle such that penetrating fixationdevice 150 is advanced through the septal wall 185. Drug delivery hereoccurs through the septum and into the left ventricle 190. In this way abolus dose is delivered to the body such that it is very concentrated inits first pass through the heart.

This is shown reasonably well in FIG. 3B which shows a plot of the drugconcentration in the heart with respect to time. Here, the drug isdelivered into the left side of the heart at time t1 and enters thecoronary arteries at a high concentration immediately thereafter at timet2. The duration of the dosage is very short such that by delivering adose over a duration delta t there is only a transient therapeuticconcentration within the heart. As the drug passes through the heart andbegins to be further diluted with the rest of the blood, the dosage willfall below the therapeutic dose. The immediate dip after the dose isdelivered is due to the lack of drug in the blood that follows the dose.

FIG. 3C shows a heart 140 with a drug delivery catheter 145 implanted inthe right atrium 160, such that the penetrating fixation device 150 isplaced within the intra atrial septum 170 and the drug delivery occursthrough the septum 170 and into the left atrial blood pool 155. In thisway a bolus dose is delivered to the body such that it is veryconcentrated in its first pass through the heart. The drug in the leftatrium will be diluted somewhat by the turbulent mixing as it passes inthe left ventricle and it will be delivered in that concentration to theheart without dilution in the rest of the patient's effective bloodvolume.

The key advantage of these device methods is that they allow a means todeliver drugs to the left blood pool of the heart transiently withouthaving a device implanted within the left side of the heart. Thisadvantage is significant. It is very difficult to have a permanentimplant in the left side of the heart because of the potentially lifethreatening problem of thrombus formation and stroke. In the left sideof the heart small clots or thrombi could be passed to the rest of thebody and obstruct critical flow to tissue such as the brain. If a deviceis implanted in the right side of the heart, the lungs will act as afilter to remove whatever clots and thrombi form and it is far lesscritical. By having a very small structure slightly penetrate theseptum, drug delivery to the chambers of the left heart is achievedwithout the issues of a left sided implant.

Delivery Adjacent to a Heart Wall

Another embodiment for local cardiovascular drug delivery, which hasparticular potential for the transient termination of arrhythmias isshown in FIG. 4. Here a simple catheter is constructed so that it isextremely flexible but has a preferred curved shape 803 that will pushit against the atrial wall in a preferred configuration afterimplantation. This can be achieved by molding a portion of the curvedportion of the catheter body 803 out of polyurethane or silicone. Thecatheter so formed is advanced into place with a rigid stylet, such thatit takes on the preferred shape after the stylet is removed. Typicallyin this instance a stylet is merely a long metal wire which may beshaped to provide stiffness for implantation of such catheters.Stiffness of the stylets can be varied by using different diameterwires, say from 0.010 inches to 0.020 inches and their shapes can bemodified by either the physician at the time of implant or during themanufacturing process. Such stylets are well known in the field ofcardiac pacing. The drug delivery catheter 800 advances into the heartfrom the superior vena cava 805 and is positioned by advancing andretracting different stylets until it is appropriately positioned. Theproximal end of the catheter 800 is connected to a subcutaneously placedimplantable pumping mechanism 806 with drug filling septum 807. The druglumen in catheter 800 may be separate from the lumen in which the styletis used for positioning purposes. The apertures along the distal portionof catheter 800 cannot be seen in this view because they are oriented sothat they are adjacent to the heart wall.

FIG. 4A shows this more clearly. Along the outer portion of the curvedcatheter there are a number of apertures 801 which allow fluid to bedelivered preferentially towards the atrial wall 802. Such a deliverycatheter would provide a means to alter a long linear region of tissuewithin the atrium transiently. This has great potential in treatingsupraventricular tachyarrhythmias.

FIG. 4B shows a cross section of the catheter shown in FIG. 4A along aregion of the curve 803 which includes apertures 801. Here the drug isshown in the catheter lumen 825 and passing into the holes 810 whichhelp define the apertures 801 in the main catheter tubing body 815. Itwill be noted that here, catheter body 815 is covered with a thin porousstructure 820 such as ePTFE which may allow adhesion of the catheter tothe heart wall in the region of the apertures over time. This may bedesirable as it may facilitate the delivery of agents to specificregions of the atrium to create transient linear regions of electricalslowed conduction and possibly electrical block. Roughening the surfaceof the catheter may be another means to promote adhesion of the catheterto the endocardial atrial surface. In other embodiments the ePTFE jacketwould not be present, and the catheter would not be roughened.

Part II: Methods and Devices for Transient Delivery of Agents to theLocal Drug Delivery Systems

Manually Triggered Drug Delivery Process

In one embodiment, a permanently implantable catheter will enable thepatient to deliver drugs to his or her atrium upon experiencingsymptoms. FIG. 5 shows such a system. The proximal end of the catheter850 systems described could be connected to a subcutaneous injectionport 855. Such injection ports are common in the literature and oftenare made of a titanium body with a silicone injection septum 860. Withsuch a device in place, a patient could self administer an injectionthrough their skin, through the silicone septum of the device, and intothe tubing which leads to the appropriate drug delivery structureembodiment. In this way, a patient recognizing an arrhythmia is able toself administer an agent to a specific location within his or her heart.By prepackaging the syringes 865, the dosages can be controlled.

An alternative approach is to provide the patient with a subcutaneousself triggered pumping device that has a reservoir filled by aphysician. These are shown in FIG. 1, FIG. 2A, FIG. 2K, FIG. 2R, andFIG. 3A. Multiple therapeutic doses could be stored in such a device.Such pumping systems are already in the European market, but have notbeen used for this application. The self triggered pumping devices canbe triggered by applying pressure to the surface of the body over thepump and depressing a diaphragm in one embodiment. In another, the pumpcould be an electronic device that is activated by the placement of amagnet over the device such as is known in the art of implantableelectrical devices.

Instead of allowing the patient to self administer agents to themselvesupon experiencing an episode, another approach is to incorporatealgorithms for identifying particular arrhythmias and delivering therapywith a microprocessor based approach as described in the prior art andliterature, which is hereby incorporated by reference. A microprocessorbased automated pharmacological defibrillator would monitor cardiacelectrical signals and deliver agents locally to the heart tissue whenthe electrical signals are determined by a programmed algorithm tosignify that the heart is experiencing an arrhythmia.

The small doses of defibrillating pharmacological agents will bedelivered to the heart tissue over a short period of time. The diffusionfrom the delivery sites inactivates the tissue electrically andterminates the arrhythmia. This system is relatively inexpensive tomanufacture.

Part III: Hybrid Therapy

Transient cardiovascular drug delivery will improve other therapies suchas implantable devices for electrical stimulation of the heart andtechniques for permanent cardiac ablation.

Transient Drug Delivery and Electrical Stimulation Devices

In the first embodiment, the drug delivery systems shown in FIG. 1 anddescribed in detail in U.S. Pat. No. 5,551,427 Altman, and in thepending application by Altman and Altman is coupled to an implantabledefibrillator. Such a system is shown schematically in FIG. 6A and FIG.6B. These systems provide the means to incorporate an algorithm thatwill allow the implantable system to identify a ventriculartachyarrhythmia and infuse antiarrhythmic agents into the ventricularseptum in order to terminate the arrhythmia.

Typically, a tiered therapy automatic implantable cardioverterdefibrillator will sense a ventricular tachyarrhythmia and identify anorganized but excessive rate as ventricular tachycardia, or VT. Toterminate the VT, the devices typically attempt to pace the heart at afaster rate than the tachyarrhythmia, entrain the heart at this higherrate, and then slow the paced rate below the tachyarrhythmia rate. Thisoften does not work, and the only alternative is to deliver a painfulhigh voltage shock to the patient to terminate the arrhythmia. Further,antitachycardia pacing has potential to accelerate the patients nativearrhythmia and induce potentially life threatening ventricularfibrillation. Both of these effects of the standard therapies for VT areless than desirable. Since the reentrant circuits that drive VT areoften located within the ventricular septum, it is possible with thesystems shown in FIGS. 6 a and 6 b to terminate these arrhythmias withlocal infusion of antiarrhythmic agents to a depth within themyocardium.

FIG. 6 a shows an implantable defibrillator 900 electrically connectedby lead 910 to electrically triggered pumping reservoir 920. Pumpingreservoir 920 is connected to a drug delivery catheter body 925 whichdelivers drug to a depth within the tissue by active fixationpenetrating drug delivery structure 930. Such drug delivery structureshave already been described here and in the art. Defibrillator 900 isalso electrically connected to implantable electrical lead 970 which hasone or more defibrillation electrodes 960 along its length, and at leastone pacing electrode 940 at its distal end. Implantable electrical leadalso has a fixation mechanism to secure the distal end of the lead atthe implantation site, which in this figure is shown to be passive tines950. Upon detecting ventricular tachycardia, the defibrillator 900 sendsan electrical signal down the lead 910 which triggers the pumpingreservoir 920 to infuse the ventricular septum with antiarrhythmicagents.

It is important that the pacing/sensing electrodes 940 are physicallyseparate from the drug delivery structure 930 for such automaticarrhythmia detection, because the infused drug will affect the abilityto measure the heart's electrical action at the site of drug delivery.

FIG. 6 b shows a very similar embodiment in which the defibrillator andpump are combined in a defibrillator/pump 980 which delivers fluid andelectrical energy down a single main lead body 990 which splits at 1000to allow for spatial separation of drug delivery structure 930 anddistal pacing/sensing electrodes 940.

This is just one embodiment of a means for coupling the transientdelivery of electrical and local pharmacological device therapies. Drugdelivery to a depth of the heart wall, to an outer surface of the heart,to the left chambers of the heart, and to long linear regions of theheart wall may be combined with electrical stimulation and sensingalgorithms to provide substantially novel and unique results. Similarsystems could be made combining: 1) local pharmacological atrialdefibrillators with state of the art DDD pacemakers or automaticimplantable cardioverter defibrillators, 2) devices to infuse drugslocally to reduce pain prior to delivering high voltage electricalenergy, and 3) devices to precondition the tissue pharmacological priorto delivering electrical energy.

Transient Drug Delivery and Cardiac Ablation

In an attempt to cure atrial fibrillation, many researchers areintroducing long linear lesions to the heart wall with differentcatheter techniques. The problem with such long lesions is that theyprevent the propagation of signals through the heart even when anarrhythmia is not present, and reduce functionality of the heart. Usinga drug delivery device has potential to provide flexibility in thecreation of these lesions which is not currently available. An exampleof this is shown in FIG. 7A.

FIG. 7A shows a region of atrial tissue 1102 with three long linearlesions 1100, 1105, and 1110, and placed such that electrical signalscan propagate between them through the atria. In the center of thesethree lesions is a single penetrating drug delivery structure 1130connected to catheter system 1140. Although the long linear lesions1105, 1110, and 1100 are insufficient to completely eliminate thepossibility of the tissue in question sustaining an arrhythmia, they arealso insufficient to substantially decrease the viability of the atrialfunction. Upon onset of an arrhythmia, antiarrhythmic drugs (amiodaroneHCl, procainimide, ibutilide, or other drugs) may be infused to a depthwithin the tissue by drug delivery structure 1130, and now all of thelesions 1100, 1105, and 1110 are effectively connected to one another bya region of slowed conduction. In this way, a small amount of drugdelivery may be combined with lesions created by ablative techniques tocomplete a region of block and terminate an arrhythmia.

FIG. 7B shows a similar hybrid therapy approach in which the catheter1150 similar to those shown in FIGS. 4, 4A, and 4B delivers agents toregions of the atrial wall. Here it intersects radio-frequency ablatedlong linear lesions 1160 and 1170 in the region where it delivers agentsto the atrial wall. This connects the two linear lesions to create animpassable line of slow conducting tissue in the atrial wall. The atriumwill not sustain an arrhythmia with the conductive pathways blocked bythis connected and impassable line of slow conducting tissue. Clearly,other variations are also possible.

The lesions shown here are intended to be instructive, but notdefinitive. Many different lesion patterns are possible and techniquesand approaches for creating lesions of this type are still underdevelopment.

Thus the reader will see that the different embodiments of the inventionprovide a means to effectively deliver agents more locally to themyocardium such that doses delivered are minimized.

They enable transient drug delivery to the tissue for treating cardiacarrhythmias, provide a means for sensing the heart, and may be combinedwith cardiac ablation and electrical cardiac sensing and stimulationdevices.

While the above description contains many specifics, these should not beconstrued as limitations on the scope of the inventions, but rather asan exemplification the inventions. Many other variations are possible.For example, the flow of liquid agents may be driven by implantableinfusion pumps with a variety of energy sources, and the device could bemade from as yet unidentified biocompatible materials. Other examplesinclude distally located electrically activated piezoelectric crystalsor electrodes to act as energy sources for drug delivery for improvingthe transport into cells, distally located ultrasound transducer forimplantation using ultrasound imaging. In addition, in the embodimentswhere bipolar sensing through the drug delivery structure is crucial, itis a simple task to add another electrode to enable bipolar sensing.

In addition, the simple penetrating designs shown in FIGS. 1, 1 a, 1 b,1 c, 1 d, 1Ea, and 1Eb could be modified slightly to provide for apenetrating structure that protrudes through the atrial wall and intothe pericardial space. By eliminating apertures along the penetratingstructure such as is done in some of the earlier embodiments fordelivery at a depth, therapeutic agents would only be delivered throughthe tissue to the pericardial space. The devices would be placed intissue regions such as the Right atrial appendage where the tissue isthick enough to support the penetration by a small structure, and theagents would be infused through the penetrating structure to the surfaceof the heart. The implantation of such a device would require carefulpositioning such that the structure does not penetrate the aorta, butthis should not be difficult.

In such a design of a small structure, such as a hollow active fixationhelix, that penetrates the tissue, the successful access of thepericardial space could be determined by monitoring the pressurerequired to drive flow through the device. Another potential approachwould be to have an electrically isolated electrode at the distal mostpoint of the penetrating structure which could be used to pace thetissue, and the pacing threshold data used to determine whether thedistal structure is in fact within the tissue, or penetrating thetissue. Such an embodiment could be useful for other embodiments allready discussed.

Further, the delivery of the agents could be performed withappropriately modified catheter shapes such that curves are located toeffect a certain position within and about the heart. Such curves in acatheter could be molded into place, or held in place by plasticdeformation of the helical coil in the region it is desired. Such curvedstructures may provide improved access to certain regions such as theright atrium, left atrium, right ventricle and left ventricle.

Further, the drug delivery catheters could be placed using steerableguiding catheters. Acute non implantable steerable catheters that can besecured to an implantable drug delivery catheter and steered using pullwires to place and position the different drug delivery cathetersdescribed. For acute use of the drug delivery catheters described theycould be modified so that they are steerable having pull wires at theouter radii of the catheter body and potentially ribbons at the cathetermidline to define the planes of bending. Many other designs are possibleand have been described in the relevant art. In applications wherestylets are to be used for the placement of a drug delivery catheter, itmay be desirable to have an independent lumen for the delivery of fluidagents such that the stylet placement does not introduce air into thesystem. This can be achieved readily by having a tube which lies inparallel with the torque coil and moves in tandem with it, within theouter catheter jacket. Other potential designs include havingmulti-lumen tubing up until the distal end of the catheter and having asmall flexible region of drug delivery tubing connected to a deployabledrug delivery structure. Many other designs are possible.

For most applications, it may be appropriate to position the componentsrelative to their implantation such that the drug delivery systems arefilled with either the appropriate drug, physiological saline, orheparinized drug solution or saline at the time of implant. This wouldmean that the catheters would be connected to the pumping systems andsensing devices prior to implantation, and in the case of applicationswhich require tunneling of the devices such as shown in FIG. 1, theconnection would occur after a tunneling procedure which would occurbefore implantation of either the device or the drug delivery system.For such pre-connected systems, an external steerable guiding catheterfor placement is attractive, as is an externally accessible stylet lumenthat is not involved in the connection of the device to the drugdelivery catheter.

Perhaps more broadening is the use for the drug delivery systemsdescribed to deliver agents for the minimization of coronary restenosis,initiation of therapeutic angiogenesis, or performing gene therapy. Suchtechniques would involve a more steady state approach for the deliveryof therapeutic agents independent of the electrical activity of theheart. However, the systems shown here incorporate many details whichare relevant for the delivery of therapeutic and diagnostic agents ingeneral. For example, a slow steady infusion of amiodarone to a depthwithin the heart, or delivery of such agents on a regular basis, mayprove to be advantageous and are enabled by the local drug deliverysystems described here.

More than one of these systems may be implanted so that they can effectnovel therapies. For example drug delivery to both the atrial andventricular walls with separate catheters coupled to either the same orseparate subcutnaeously implanted drug delivery pumps and reservoirscould be configured such that the drug delivery is controlled such thatdelivery to each catheter is controlled independently.

The drug delivery systems described here can be used acutely duringbeating heart cardiac surgery to introduce a temporary stop or markedslowing of the heart. Such induced bradycardia would provide a quiescentheart for very short periods so that delicate surgical procedures may beperformed. Procedures as common and important as suturing during bypasssurgery are one example of techniques that would be improved by suchslowing of the heart. One example of implementation of this approachwould involve a infusion of adenosine at a depth within the heart tissueadjacent to the AV node or infranodal structures with acute versions ofthe catheters shown in FIGS. 1A to 1F, followed after the quiescentperiod with temporary ventricular pacing to control haemodynamics.Additional agents could be given systemically to slow ventricularautomaticity and the delivery of agents to introduce AV nodal blockadeor infranodal blockade to result in a more marked slowing of the heartthat could be rapidly reversed with ventricular pacing. The use of thecatheter systems and local drug delivery schemes described in thisdisclosure are relevant for transient delivery for such slowing of theheart for improvement of surgical procedures.

Conduction between the atria and the ventricles can be stopped or slowedby many techniques. Reversible conduction block at a site within theheart such as between the atria and ventricles may be introduced by theinfusion of agents to slow or stop conduction into the heart tissueadjacent to the AV node or infranodal structures, the application ofmechanical or thermal stresses, or the delivery of high rate pacingenergy or direct current depolarization. For simplicity, this discussionwill focus on the infusion of agents to introduce atrioventricularblock. Many agents have potential to induce conduction slowing and blockbetween the atria and ventricles. Chilled saline or other physiologicalfluid, antiarrhythmic agents, cardioplegic fluids, ringers solution, andelectrolyte solutions such as potassium to depolarize the cells may beused to introduce slowed conduction or to stop conduction altogether.Drugs that predominantly prolong refractoriness, or time before a heartcell can be activated, produce conduction block including the class IAantiarrhythmic agents (quinidine, procainimide, and disopyrimide) orclass IC drugs (flecamide and propafenone). The class III antiarrhythmicagents (sotolol or amiodarone) prolong refractoriness and delay or blockconduction. Other antiarrhythmic agents may also be used to introduceconduction block, as may the various cardioplegic fluids traditionallyused for whole heart cardioplegia.

These agents could be infused to a depth within the heart tissueadjacent to the AV node and infranodal structures with many of theinfusion catheter systems described in my prior patent Altman,Implantable Device for the Effective Elimination of CardiacArrythmogenic Sites, U.S. Pat. No. 5,551,427 (Sep. 3, 1996). Here, animplantable substrate for local drug delivery at a depth within theheart is described. The patent shows an implantable helically coiledinjection needle which can be screwed into the heart wall in theventricles and connected to an implanted drug reservoir outside theheart. This system allows injection of drugs directly into the wall ofthe heart by merely injection of drugs through the skin into thereservoir. The patent also shows a helical coil coated with coatingwhich releases drug into the myocardium. This drug delivery may beperformed by a number of techniques, among them infusion through a fluidpathway, and delivery from controlled release matrices at a depth withinthe heart. Pending application Ser. Nos. 09/057,060 by Altman and08/881,685 by Altman and Altman, describe some additional techniques fordelivering local pharmacological agents to the heart.

Temporary ventricular pacing will be desirable to control hemodynamics.Because the rate of the heart will be substantially slowed, and itsautomaticity may be reduced or even eliminated, it is important to havetemporary pacing to provide electrical stimuli to allow ventricularcontraction to be controlled. Temporary pacing wires are well known tothose familiar with cardiac electrophysiology and may be placedtransvenously in the right ventricular apex or epicardially at eitherventricular apex to stimulate the heart with pacing energy.

The first method of implementing this transient stopping of the heartinvolves using any of the techniques described to create a region ofblock before a delicate surgical procedure (such as a distal coronaryanastamosis) is to be performed, and controlling the heart by varyingthe rate at which pacing pulses are delivered to the right or leftventricle. The heart rate could then be lowered substantially to a rateof around 20 beats per minute, or the heart may be stopped for a shortperiod of time on the order of 10-60 seconds. The slowed rate of thepacing device could be timed such that a higher rate would resume aftera short period of time and minimize the risk of hemodynamic instability.

The second method of implementing this transient stopping of the heartis similar to the first, but eliminates the cause of atrioventricularblock when the slowing of the heart is not required. For an infusionsystem which delivers anti-arrhythmics to introduce atrioventricularblock, the infusion would be stopped when the slowed conduction, andhence the AV block, are not desired. Such an approach eliminates thepossibility of having a locally infused block producing agent fromreaching a systemic concentration that would have an effect on the hearttissue.

FIG. 8 shows a schematic of such a system. Here the patient 1 is shownadjacent to the infusion system 885 which controls the infusion of theblock producing agent and the delivery of pacing energy to the rightventricle 801 to control hemodynamics. Infusion system 885 consists of aphysician interface 810 which controls the activation of pacing unit 816and pressure infusion unit 821 with a reservoir of block producingagent. Activation of pacing unit 816 delivers pacing pulses throughtemporary ventricular pacing lead 825 to the heart wall of the rightventricle 801. Activation of infusion unit 821 delivers either a setpressure or a set flow rate of block producing agent to the region ofthe interventricular septum 835 substantially adjacent to the HIS bundle803 through tissue penetrating infusion catheter 830, shown here to befixed high on the interventricular septum 835. In other embodiments, apenetrating element could access the region substantially adjacent tothe HIS bundle through the right atrium, or the region of theatrio-ventricular node 804. In still other embodiments, the sino-atrialnode 805 may be the region targeted for infusion to eliminate initiationof cardiac rhythm.

In FIG. 8, the physician interface 810 includes a switch that turns onthe infusion unit 821 and turns on the pacing unit 816 to controlhemodynamics. When the surgeon wants to stop the heart to perform aprocedure, the surgeon may either slow the ventricular pacing to slowthe heart or stop the pacing to stop the heart. In this system, theability to stop the heart for a set period of time is timed out inapproximately 30 to 60 seconds and once timed out prevents re-initiationof the system until a set recovery period has passed. The time betweeninduced heart stoppages may be limited so as not to fall below 60seconds. Also shown in FIG. 8 is a respirator system 850, which includesa respiration controller and is connected through the ventilation hose851 to ventilation mask 852 to provide air to the patient duringsurgery. The respirator mask could easily be replaced with eithertracheal intubation or even single lung bronchial intubation, and isused here diagrammatically. The respirator system is connected to theinfusion system 885 by cable 853, and is controlled by the infusionsystem 885 to cease respiration when desired by the operator. Theoperator may turn on and off various algorithms set on the physicianinterface using a footswitch if so desired.

FIG. 9A shows a first embodiment of the use of the system shownschematically in FIG. 8. FIG. 9A is a chart of the cardiac electrogram902 adjacent to the output 904 of the pacing unit 816 and the output 906of the infusion system 885. Electrogram 902 shows an atrial p wave 908,an inherent ventricular depolarization referred to as the QRS wave 910,a pacing spike 912, and a paced ventricular depolarization 914. Pacingdevice output line 904 shows a series of pacing spikes 905 beingdelivered by the temporary ventricular pacing lead 825. The pacingspikes appear in the cardiac electrogram 902 as sensed pacing spikes912. Infusion system output line 906 shows a stepped increase ininfusate flow rate Q or pressure P. The heart is paced to keep itbeating for the entire time course shown in FIG. 9A. Here it should benoted that block is introduced after the infusion is turned on as shownby infusion system output 906, and the right ventricle must be paced,beginning with pacing spike 912, to maintain hemodynamic stability. Inthis embodiment the infusion is maintained into the region substantiallyadjacent to the AV node and/or HIS bundle to produce atrioventricularblock for the duration of the surgical procedure, and the heart iscontrolled by altering the timing of the ventricular pacing. When it isdesirous to slow or stop the heart, the pacing is slowed or stopped, atthe same time that the respirator is turned off to eliminate the heartmotion and obstruction due to the lungs. The p waves 908 continueunabated and indicate that the system described in FIG. 8 and controlledaccording to FIG. 9A is set up primarily to control the motionassociated with the ventricles (because the heart-stopping infusion isinjected in the vicinity of the HIS bundle), and the paced electricalactivity of the atrium is not substantially affected. The pacing may beslowed to the range of 10 to 30 beats per minute, and is illustrated inFIG. 9 a to be about 20 beats per minute, with about three secondsbetween pacing spikes. Thus a slow-beating period in which the pacingsystem paces the heart while the infusion system suppresses the naturalheartbeat is created by the system programmed to operate in accordancewith FIG. 9A. Circuitry and/or control system algorithms will preventthe surgeon from slowing or stopping the heart for periods longer thanthe patient will tolerate without adverse effects. Where the controlsystem includes a computer, the computer will be programmed to recordthe start time and duration of each heart stoppage, and to preventapplication of heart-stopping infusion for a set time after a previousapplication, or to initiate pacing after a set period of time afterapplication.

FIG. 9B illustrates another use of this system to affect the heart beatof a patient. Here, the infusion system is turned on to stop or slow theheart for a preset time period that is timed out (limited in duration bythe system). The system will allow the operator to stop the heart frombeating only for a certain safe time period, after which theheart-stopping infusion is terminated and pacing commences to restorehemodynamic stability. (There is a portion of the strip 966 which is notshown in order to compress the time period time 1 within the givenspace.) In FIG. 9B, the p waves 908 continue unabated and indicate thatthe system described in FIG. 8 and controlled according to FIG. 9B isset up primarily to control the motion associated with the ventricles(because the heart-stopping infusion is injected in the vicinity of theHIS bundle). A non-beating period, during which the ventricles do notcontract, is produced when the system is operated in accordance withFIG. 9B. In other embodiments, block producing agents may be deliveredto the region substantially adjacent to the sino-atrial node 805 toeliminate atrial contractions as well. In still other methods used tosupport specific cardiac surgeries, block producing agents are deliveredonly to the sino-atrial node. While operating the system in accordancewith FIG. 9A, the respirator may be controlled by the infusion system,such that when it is desirous to eliminate heart motion, the infusionsystem is turned on at the same time that the respirator is turned off.This eliminates the rising and falling of the heart caused by theinflation of the lungs adjacent to and beneath the heart, and minimizesthe obstruction of the surgical field by the expanded lung tissue.

FIG. 10 shows a schematic of a system in which the systems areintroduced epicardially to the surface of the heart. Epicardial deviceshave benefits to the cardiac surgeon who has access to the surface ofthe myocardium. Here the patient 1001 is shown adjacent to the infusionsystem 885 which controls the infusion of the block producing agent andthe delivery of pacing energy to the heart to control hemodynamics. Therespirator system 850 includes a respiration controller and is connectedthrough the ventilation hose 851 to ventilation mask 852 to provide airto the patient during surgery. The respirator system is connected to theinfusion system 885 by cable 853, and is controlled by the infusionsystem to cease respiration when desired by the operator.

In this embodiment, the fluid delivery system is connected to the heartepicardially and secured to the heart by a fixation structure 1005,shown here to be a helix, although sutures, barbs, adhesives, and evenbonding agents could also be used. The fluid delivery may be throughsuch a fixation structure to a region within that portion of themyocardium with devices similar to those described in pending U.S.application Ser. Nos. 08/881,685 and 09/057,060 and in issued U.S. Pat.No. 5,551,427 or it may be through a separate thin walled tube that isintroduced to a depth within the heart. The catheters are inserted intothe epicardial space preferably with minimally invasive techniques whereminimally invasive heart surgery techniques are to be used to perform acoronary bypass surgery or other cardiac surgery (such surgery may beaccomplished through endoscopic access ports using robotic catheters assmall as two millimeters in diameter). Of course, the technique can beused during open heart surgery as well. The infusion system is operatedin accordance with FIG. 9 a or 9 b to control movement of the heartduring surgery.

Either a hollow fixation structure, or a separate flexible thin walledstructure could be advanced to a depth within the heart muscle. Here,the fluid agents are delivered from reservoir and pressure infusion unit821 through catheter 1030 and into the heart adjacent to the anteriorinterventricular artery 1008 such that agents may be delivered adjacentto the HIS bundle. The delivery may be accomplished through apenetrating tube which will be more readily described in FIG. 11.Temporary pacing to provide hemodynamic stability is provided byepicardial pacing lead 1025 shown fixed to the apex of the heart withhelical fixation electrode 1010. Such epicardial pacing electrodes arewell known in the art, and are commercially available.

FIG. 11 shows a partially sectional view of one embodiment of theepicardial fluid delivery means shown in FIG. 10. By providing astructure 1120 to stabilize the heart while flexible delivery tube 1122is secured to the heart by a helical fixation structure 1118, the deviceenables controlled epicardial delivery of fluid agents to a depth withinthe heart. Shown here is a stabilizing structure 1120 to controladvancement of a penetrating element to a depth within the heart. In thepreferred open chest embodiment the stabilizing structure 1120 and itscatheter body 1112 is made much like a peel away catheter introducersuch that after the centrally located penetrating fluid delivery elementis placed, the stabilizing structure can be removed in two parts fromeither side of the outer body of the infusion catheter 1108. Thepenetrating fluid delivery element in the preferred embodiment forepicardial delivery is shown here to be a thin flexible tube 1122supported by a coaxial needle 1124. After positioning the fluid deliverytubing 1122 at a depth within the tissue, the coaxial needle 1124 isremoved. Tubing is held in place by the fixation helix 1118 which issized around 0.100″ to 0.250″ in diameter and is comparable to anepicardial screw in pacing lead fixation helix. Fluid agents are thendelivered through tubing 1102 into resealable housing 1104 and throughtubing 1122 to a depth within the heart tissue. After coaxial needle1124 is removed by retracting needle handle 1125 from resealable chamber1104, the flexible tubing 1122 will be less likely to damage themyocardium as the heart contracts. Tubing 1122 may be made of manymaterials including polyurethane, silicone, nylon, and other polymers.

The use of this device for delivering fluids in a controlled fashion toa depth within the heart involves a number of steps. Support structureis placed against the heart, and the resealable housing 1104 is rotatedrelative to the support structure counterclockwise to advance thefixation helix 1118 by transferring torque through the torque coil 1110through the torque transmission sleeve 1114 and to the centrally locatedcoil 1116. The coil 1110 is mechanically attached to the housing 1104 bya crimp structure 1106 which is bonded to outer tubing body 1108. All ofthese structures will rotate relative to the stabilizing structure 1120and its tubing 1112. The advancement of fixation helix 1118 is achievedby its rotation relative to the advancement structures 1128 shown hereto be part of the peel away stabilizer 1120 and its tubing 1112.Advancing the helix 1118 will result in penetration to a depth withinthe tissue of needle 1124, and tubing 1122 to a depth within the heart.After penetration, the needle 1124 is removed by extracting needlehandle 1125 from resealable chamber 1104, possibly formed with asilicone septum, and the peel away catheter 1104 and stabilizer 1120 areremoved.

The method of inducing heart stoppage or slow beating is intended toprovide a quiescent period in the movement of heart so that surgicalprocedures may be accomplished on a stationary heart, rather than abeating heart. The conduction block producing step and the slow beatingor non-beating period are used by the operator to perform varioussurgical procedures or parts of the procedures, such as performing adistal anastomosis of bypass grafts during cardiac bypass surgery.

Other modifications and variations can be made to the disclosedembodiments without departing from the subject of the invention asdefined in the following claims. For example, fluid agents could bedelivered to one or more specific sites substantially adjacent toparticular points within the hearts conduction system. Regions such asthe AV node, Bachman's bundle, the SA node, the HIS bundle, and thelower ventricular septum have been considered, but other regions alongthe Perkinje network are also possible. In some embodiments it also maybe desirable to deliver agents to create block at both the SA node andthe AV node.

Further, the delivery may be controlled with a variety of pumpingsources, and the fluid delivered may be a variety of active agents thatwill slow conduction. Embodiments of this approach which use electricalstimulation to introduce transient block would involve the placement ofactive fixation electrode catheters at the sites currently described forinfusion, and such catheters could be made similar to the infusioncatheters described.

Further, the catheters described for drug infusion to a depth within themyocardium may include a variety of different sensors. This isparticularly relevant for transvascular catheter approaches. Otherexamples include distally located electrically activated piezoelectriccrystals to act as energy sources for drug delivery and distally locatedultrasound transducer for implantation using ultrasound imaging. Inaddition, in the embodiments where bipolar sensing through the drugdelivery structure is crucial, it is a simple task to add anotherelectrode to enable bipolar sensing. In addition small positioningtransducers such as those developed by Biosense, Inc. and thosedescribed in U.S. Pat. No. 5,769,843 could be included in the distal endof the catheter system to improve the localization of the distal end ofthe catheter within the myocardium. Although such transducers may beincorporated easily in the design of such a catheter system, anotherembodiment may involve passing the drug delivery catheter systemsdescribed here through a guiding catheter with or without suchtransducers on their distal end, or passing systems with suchtransducers within a larger lumen of the drug delivery catheter systemsdisclosed here.

In this last example, where a catheter with a transducer on its distalend, is passed within a drug delivery catheter, the central transducercatheter could even electrically couple with the distal end of the druginfusion catheter such that the central catheter may be in electricaland thermal contact with the heart tissue. This could be achieved byhaving a metal engagement feature on the distal end of the twocatheters, such as a collar that fits within an expandable coil. Thismay have particular advantages in combing the catheter sensor technologyof the magnetic coil positioning systems under development by Biosense,Inc.

In addition, the specific design described for epicardial delivery offluidic agents during cardiac surgery may be used to deliver othertherapeutic agents, molecules, genes, gene therapy preparations, viralvectors, cellular tissue, myocytes, angioblasts, collagen materials,micro drug delivery systems, and the like.

Accordingly, the scope of the invention should be determined not by theembodiments illustrated, but by the appended claims and their legalequivalents.

1. A method for controlling the motion of a heart having a heart wall,said method comprising the steps of: inserting a catheter having adistal end with a fixation structure transcutaneously into a chamber ofthe heart of the patient; attaching the distal end of the catheter tothe heart wall using a fixation structure; injecting cardioplegic fluidstransendocardially to a depth within the heart wall at a site in themyocardial conduction system adjacent to the HIS bundle through thecatheter to produce a transient conduction block locally at the site inthe myocardial conduction system to stop normal contraction of theheart; and pacing the heart to provide hemodynamic stability when normalcontraction is required for hemodynamic stability.
 2. The method ofclaim 1 wherein the step of producing a transient conduction blockcomprises infusing a block producing agent into the site, wherein theblock producing agent is selected from the group consisting ofantiarrhythmic agents, cardioplegic fluids, saline, ringers solution andcombinations thereof.
 3. The method of claim 1 wherein the step ofproducing a transient conduction block is followed by the step ofperforming a distal anastomosis during cardiac bypass surgery.
 4. Themethod of claim 1 comprising the further steps of giving the patientdoses of agents to lower automaticity of cardiac myocyte contractionsfor the duration of a medical procedure.
 5. The method of claim 1comprising the further steps of: providing a respirator and operablyconnecting the respirator to the patient; operating the respiratorduring a medical procedure; and turning off the respirator at the sametime that pacing is slowed or stopped to provide for reduced musclemotion.